Cancer Risk Assessment

Judith A Westman MD

Clinical Director

Division of Human Genetics

Cancer risk assessment is a multi-step process

Provide Provide post-test post-test counselincounselin

g and g and follow-upfollow-up

Identify Identify hereditarhereditar

y risk y risk patientspatients

Provide Provide risk risk

assessmenassessmentt

Provide Provide informed informed consentconsent

Select and Select and offer testoffer test

Disclose Disclose resultsresults

The cancer family history is the key to:

Accurate risk assessment

Effective genetic counseling

Appropriate medical follow-up

Taking a cancer family history

• Obtain at least a three-generation pedigree• Ask about all individuals in the family

and record:– age at cancer diagnosis, age at and cause of

death– primary vs metastatic cancer– precursor lesions, bilateral cancer

• Record ethnicity and race• Verify with medical records when possible

Breast Cancer

Best model for risk assessment

Cancer Risk Assessment (for high risk breast cancer)

• Attempts to assist patient in understanding:– Medical facts– Mode of inheritance– Risk of getting breast and/or ovarian cancer (again)– Implications for daily life

• Options for dealing with the risk– Breast surveillance– DNA testing– Prophylactic mastectomy and/or oophorectomy– Chemoprevention (tamoxifen, SERM, OCP)

Gail model• Breast Cancer Detection and Demonstration

Project– 2852 cases, 3146 matched controls– J Natl Cancer Inst 81:1879-86, 1989

• Used to determine lifetime breast cancer occurrence risk

• Used to determine appropriateness for prophylactic tamoxifen therapy

• Incorporates– Age– Reproductive history– Benign breast disease history– Breast cancers in mother or sisters

Pitfalls of Gail model

• Does not include other cancers in model– Ovarian, pancreatic, thyroid, male breast

• Does not include second-degree relatives– Aunts, uncles, grandparents

• Does not include paternal side

• Does not include age of breast cancer diagnosis in relatives

Cancer and Steroid Hormone Study

Three-generation pedigree

Breast Ca,

dx 41

35

German/Polish English/Irish

Breast Ca, dx 49

d. 80

67 5565Diabetes,

dx 45

52

30

d. 70 d. 85

5962

d. 52

Claus risk for breast cancer

• Claus table for two second-degree relatives• Probability to age 79 = 20.9%

– To age 39 = 2.4%– To age 49 = 6.1%– To age 59 = 11.4%– To age 69 = 16.9%

• Risk can be “used up”– A 59 year old woman with no cancer

• 20.9% risk of breast cancer by age 79?• Or 9.5% risk of breast cancer by age 79?

MYTHS:• “Cancer on the father’s

side of the family doesn’t count.”

• “Ovarian cancer in the family history is not a factor in breast cancer risk.”

• “The most important thing in the family history is the number of women with breast cancer.”

Misconceptions about family history

TRUTHS:•Half of all women with hereditary risk inherited it from their father.•Ovarian cancer is an important indicator of hereditary risk, although it is not always present.•Age of onset of breast cancer is more important than the number of women with the disease.

Hereditary Breast and Ovarian Cancer

Sporadic

BRCA1 (62%) Other Other

genesgenes

(16%)(16%)

BRCA2 (32%)

7-10%7-10%

Hereditary

ASCO

Features that indicate increased likelihood of having BRCA mutations

• Multiple cases of early onset breast cancer

• Ovarian cancer (with family history of breast or ovarian cancer)

• Breast and ovarian cancer in the same woman

• Bilateral breast cancer

• Ashkenazi Jewish heritage

• Male breast cancer

ASCO

BRCA1-Associated Cancers: Lifetime Risk

Possible increased risk of other cancers (eg, prostate, colon)

Breast cancer 50%85% (often early age at onset)

Second primary breast cancer 40%60%

Ovarian cancer 15%45%

ASCO

BRCA1-Linked Hereditary Breast and Ovarian Cancer

Noncarrier

BRCA1-mutation carrier

Affected with cancer

Breast, dx 59

Breast, dx 45d. 89

92 86

73 68 Ovary, dx 59d. 62

71

Breast, dx 36

36

ASCO

BRCA2-Associated Cancers: Lifetime Risk

Increased risk of prostate, laryngeal, and pancreatic cancers

(magnitude unknown)

breast cancer (50%85%)

ovarian cancer (10%20%)

male breast cancer (6%)

Westman experience (1996-2009): 5 positive results

TP53 mutation R181C

BrCadx 43Lymphoma,

9

Brain, 46

Renal Ca, 81

Bone, 18 Renal, 51

Brain, 12

Who to test?• Use software tool (BRCAPro)

– Individual’s cancer status– History of breast and ovarian cancer in 1st and 2nd

degree relatives– Number of affected vs unaffected in family– Risk >10% with clear benefit

• Person affected with cancer– Early onset breast preferably– Ovarian at any age

• Any Ashkenazi Jewish or Icelandic person• Any person in family with known mutation• Most health insurers have published

guidelines

Who to test?

Breast Ca,

dx 41

35

German/Polish English/Irish

Breast Ca, dx 49

d. 80

67 5565Diabetes,

dx 45

52

30

d. 70 d. 85

5962

d. 52

Risk assessment

• 35 year old daughter– Claus, 19.5% lifetime risk for breast cancer– Risk of carrying BRCA gene = 2-9%

• 67 year old father– Risk of carrying BRCA gene = 5-9%

• 62 year old aunt, cancer at 41– Risk of carrying BRCA gene = 9-15%

Upper risk figures from Myriad Laboratory, lower from BRCAPro

Use of pathology to refine risk

•BRCA1 breast tumors– 80% basal subtype (triple negative)– DCIS rare in carriers vs controls (now under

reconsideration)

•BRCA2 breast tumors– Typical distribution of molecular subtypes

•Ovary– Predominantly papillary serous adenocarcinoma– Prognosis may be better than for sporadic ovarian

cancerNarod SA, Offit K J Clin Oncol 2005;

23:1656-1663

BRCA risk modifiers

• Family history alone– 3-7%, breast– 23% with pancr

• With path– 7-10%

Breast, 70s

Pancr, 73

Breast, 35

basal

Clinical Management of BRCA Mutation-Positive Patient

Positive BRCA1 or BRCA2 test result

Possible testing for other adult relatives

Increasedsurveillance

Prophylacticsurgery

Lifestyle changes

Chemo-prevention

ASCO

Primary prevention of breast cancer

• Prevents cancers from occurring in the first place

• Prophylactic mastectomy• Lifestyle changes

– Breast feeding (BRCA1)– Small family size (BRCA2)– Exercise, maintain stable weight

• Pre-menopausal oophorectomy (~40 years)• Chemoprevention

Chemoprevention of Breast Cancer in BRCA1/2 Carriers

Tamoxifen

Risk reduction of 50% or more in both BRCA1 and BRCA2 carriers

Gronwald J et al, Int J Cancer 2006;118(9):2281-4

Secondary prevention of breast cancers in BRCA1/2 carriers

• Early detection of tumors when surgery alone would be feasible

• Early clinical surveillance (begin at age 25)

– Clinical breast exams every 6-12 months

– Annual mammography

– Monthly breast self-exams

• Breast MRI instead of mammography

Narod SA, Offit K J Clin Oncol 2005; 23:1656-1663

Cancer risk reduction with prophylactic surgery

Domchek and Weber, Oncogene 2006; 25:5825-5831

Modifying risk for relatives

56, Breast, 51Ovarian, 51

d. 49Breast, 44

58Fallopian tube,

53

BRCA1 +BRCA1 + BRCA1 -

BRCA1 -

Other breast cancer syndromes

• Li Fraumeni syndrome– Clearance of individual if mutation negative

and mutation is known in family– Few prophylactic options available for

mutation positive

• Cowden syndrome– Clearance of individual if mutation negative

and mutation is known in family– Few prophylactic options available for

mutation positive

Colorectal Cancer

Colorectal cancer

• 5% strongly inherited risk– Familial adenomatous polyposis– MUTYH-associated polyposis– Lynch syndrome (hereditary nonpolyposis

colorectal cancer)• Colon cancer, predominately right sided early

onset (60%)• Endometrial cancer (50% of women)• Ovarian cancer (10-15% of women)

• Genetic testing available for all

Risk alteration in hereditary CRC

• Clearance if individual is mutation negative and mutation is known in family

• Mutation positive– FAP

• Prophylactic colectomy, other sites problematic

– MAP• Prophylactic colectomy, not known to affect other

sites

– Lynch• Annual colonoscopy, hysterectomy/oophorectomy

Cancer and Life Insurance

Actuarial fairness

• Usually, lower premiums for women vs men• In breast cancer risk

– Higher premium for women with higher risks of dying from breast cancer

• Adverse selection– Individuals with known high risk purchase more

insurance– Individuals with known lower risk do not purchase as

much insurance

Philadelphia group

• Pricing term insurance in BRCA1/2 • Markov model• Both written when more medical uncertainty

present about BRCA1/2 risks– Used 65% lifetime breast cancer risk– Used 40% lifetime ovarian cancer risk

• Suggest gathering as much information about family history as possible during the underwriting process– Include all relatives with cancer and ages of onset

Subramanian K et al (1999), J Risk Insur 66:531; Lemaire J et al (2000), N Am Actuarial 4:75

“Genetic testing, adverse selection, and the demand for life insurance”

• Salt Lake City• 105 women in large BRCA1 family, 18-55 yr old,

no personal cancer hx, no employer life insurance– 27% tested positive for BRCA1 mutation– 62% employed– 66% with life insurance

• $83,750 average policy

– No correlation with immediate family history or mutation status

• No evidence of adverse selection

Zick et al (2000), Am J Med Genet 93:29

“Life insurance and breast cancer risk assessment” (2003)

• Philadelphia group again• 636 women with risk assessment (72% insured)

– 238 underwent testing – 109 individuals with positive BRCA1/2

• 55% with significant fear of life insurance discrimination• No reports of denial or cancellation after counseling• 27 increased coverage (4%)

– 9 pos, 5 neg, 13 untested

• 6 decreased (1%) – 1 pos, 2 neg, 3 untested

K Armstrong et al (2003), Am J Med Genetics 120A:359

Genetic Information Nondiscrimination Act (2008)

• Prevents health insurers from denying coverage, adjusting premiums, or otherwise discriminating on the basis of genetic information. – Group and self-insured policies

• Health insurers may not request that an individual undergo a genetic test.

• Employers cannot use genetic information to make hiring, firing, compensation, or promotion decisions.

• Sharply limits a health insurer's or employer's right to request, require, or purchase someone's genetic information.

• Language for life insurers?

Points to ponder (1)

• Unfounded fear of life insurance discrimination may reduce use of risk assessment and preventive services

• In the absence of genetic testing results, family history of first- and second-degree relatives is effective in establishing risk. First-degree relatives alone are insufficient.

Points to ponder (2)

• Mutation negative individuals should be considered for standard underwriting.

• Risk reduction intervention in mutation positive individuals may cause reduction in overall mortality, benefitting patients and insurers alike.

• Use of primary prevention methods could facilitate standard underwriting for mutation positive individuals.